Application of a Treg gene signature to measure disease trajectory and treatment response in type 1 diabetes

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Abstract Summary

Insufficient regulatory T cell (Treg) control of autoreactive T cell-mediated destruction of beta-cells contributes to type 1 diabetes (T1D). Multiple therapeutic strategies to restore a normal immunoregulatory balance and stop T1D progression are in development and testing. However, a major challenge has been defining biomarkers that can prospectively identify subjects most likely to benefit from immunotherapy and/or measure intervention effects on immunity. We previously found that Tregs from children with new-onset T1D have an altered gene signature compared to healthy controls, suggesting that this could be a useful biomarker to monitor immunoregulation. Here we investigated whether the Treg gene signature is also altered in T1D adults, finding significant differences in new-onset and cross-sectional cohorts compared to controls (AUC=0.830, AUC=0.953). Furthermore, we also found that significant differences in the Treg gene signature are detected in unfractionated peripheral blood mononuclear cells, with statistical power increased by including genotype for T1D-associated SNPs (e.g. signature + Cd25 rs2104286 AUC=0.996). Treg gene signatures in T1D were distinct from those with T2D, indicating disease-specific Treg alterations. We further tested the predictive potential of the Treg gene signature by longitudinal testing in a phase I/II clinical trial of immunotherapy with ustekinumab (aIL-12/23p40). When looking at the change in Treg gene signature between weeks 0 and 40, we found an algorithm that could accurately discriminate between patients who had slow versus rapid c-peptide decline (AUC=0.818). Moreover, when examining data at week 40 alone there was a near perfect separation of slow versus rapid c-peptide decline subjects, possibly indicating a restoration of immunoregulatory balance in subjects who responded to ustekinumab. Overall these data confirm that Treg gene signature measurement is a simple and useful biomarker to measure immunoregulatory status and could possibly be useful for predicting disease trajectory, as well as stratifying and monitoring immunotherapy patients.

Submission ID :
IDS80205
Submission Type
Abstract Topics

Associated Sessions

University of British Columbia
Department of Medicine & Centre for Heart Lung Innovation, University of British Columbia, and Prevention of Organ Failure (PROOF) Centre of Excellence, St. Paul’s Hospital, Vancouver, BC, Canada
University of British Columbia and BC Children’s Hospital Research Institute, Vancouver, BC, Canada
Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA, USA
University of Toronto
Department of Surgery, The University of British Columbia, and Child & Family Research Institute, Vancouver, Canada.
University of British Columbia
Department of Medicine & Centre for Heart Lung Innovation, University of British Columbia, and Prevention of Organ Failure (PROOF) Centre of Excellence, St. Paul’s Hospital, Vancouver, BC, Canada
University of British Columbia

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KEY DATES

Event dates:
Thursday 25 October - Monday 29 October 2018

Abstract submission deadline:
Monday 14 May 2018

Abstract notification:
July 2018

Early registration deadline:
Monday 3 September 2018

Registration deadline:
Monday 15 October 2018

Contact
British Society for Immunology
+44 (0)20 3019 5901
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